Multiple sclerosis (MS) is a chronic, neurological, autoimmune, demyelinating disease. MS can cause blurred vision, unilateral vision loss (optic neuritis), loss of balance, poor coordination, slurred speech, tremors, numbness, extreme fatigue, changes in intellectual function (such as memory and concentration), muscular weakness, paresthesias, and blindness. Many subjects develop chronic progressive disabilities, but long periods of clinical stability may interrupt periods of deterioration. Neurological deficits may be permanent or evanescent. In the United States there are about 250,000 to 400,000 persons with MS, and every week about 200 new cases are diagnosed. Worldwide, MS may affect 2.5 million individuals. Because it is not contagious, which would require U.S. physicians to report new cases, and because symptoms can be difficult to detect, the incidence of disease is only estimated and the actual number of persons with MS could be much higher.
The pathology of MS is characterized by an abnormal immune response directed against the central nervous system. In particular, T-lymphocytes are activated against the myelin sheath of the neurons of the central nervous system causing demyelination. In the demyelination process, myelin is destroyed and replaced by scars of hardened “sclerotic” tissue which is known as plaque. These lesions appear in scattered locations throughout the brain, optic nerve, and spinal cord. Demyelination interferes with conduction of nerve impulses, which produces the symptoms of multiple sclerosis. Most subjects recover clinically from individual bouts of demyelination, producing the classic remitting and exacerbating course of the most common form of the disease known as relapsing-remitting multiple sclerosis.
MS develops in genetically predisposed individuals and is most likely triggered by environmental agents such as viruses (Martin et al., Ann. Rev. Immunol. 10:153-187, 1992). According to current hypotheses, activated autoreactive CD4+ T helper cells (Th1 cells) which preferentially secrete interferon-gamma (IFN-γ) and tumor necrosis factors alpha/beta (TNF-α/β), induce inflammation and demyelination in MS (Martin et al., supra). Available data suggest that the predisposition to mount a Th1-like response to a number of different antigens is an important aspect of MS disease pathogenesis. Proinflammatory cytokines (such as IFN-γ, TNF-α/β) and chemokines secreted by Th1 cells contribute to many aspects of lesion development including opening of the blood-brain-barrier, recruitment of other inflammatory cells, activation of resident glia (micro- and astroglia) and the effector phase of myelin damage via nitrogen and oxygen radicals secreted by activated macrophages (Wekerle et al., Trends Neuro Sci. 9:271-277, 1986) (Martin et al., supra).
The peripheral activation of autoreactive lymphocytes via molecular mimicry (Wucherpfennig and Strominger, Cell. 80:695-705, 1995; Gran et al., Ann. Neurol. 45:559-567, 1999) is a critical prerequisite for T cell migration into the CNS compartment (Calabresi et al., Ann. Neurol. 41:669-674, 1998). Only activated T cells expressing the necessary adhesion molecules are able to migrate across the blood-brain-barrier. It has been hypothesized that T lymphocytes in MS patients as well as in models for MS such as experimental allergic encephalomyelitis (EAE; in particular in SJL mice, see Encinas et al. Nature Genet. 21:158-160, 1999) differ from non-susceptible individuals by being in a different state of activation (Calabresi et al., supra), as the cells enter the cell-cycle more readily, stay longer in growth phase, may exhibit defects in apoptosis pathways (Zipp et al., Ann. Neurol. 43:116-120, 1998), or are in vivo activated as indicated by higher mutation rates in the hypoxanthine-phosphoribosyl transferase gene in myelin-specific T cells (Allegretta et al., Science. 247:718-721, 1990).
The status of MS patients can be evaluated by longitudinal, monthly follow-up of magnetic resonance (MRI) activity in the brain of MS patients. MRI offers a unique set of outcome measures for phase I/II clinical trials in small cohorts of patients, and is thus well suited to establish data for proof of principle for novel therapeutic strategies (e.g., see Harris et al., Ann. Neurol. 29:548-555, 1991; MacFarland et al., Ann. Neurol. 32:758-766, 1992; Stone et al., Ann. Neurol. 37:611-619, 1995). There are currently four approved treatments for relapsing-remitting MS, three types of IFN-β (the Interferon-B multiple sclerosis study group, Neurology. 43:655-661, 1993; the IFNB Multiple Sclerosis Study Group and the University of British Columbia MS/MRI Analysis Group, Neurology. 45:1277-1285, 1995; Jacobs et al., Ann. Neurol. 39:285-294, 1996), and copolymer-1 (Johnson K P, Group. tCMST, J. Neurol. 242:S38, 1995). Treatment failures have been linked to the development of neutralizing anti-IFN-β antibodies, although their role is also not completely understood at present (the IFNB Multiple Sclerosis Study Group and the University of British Columbia MS/MRI Analysis Group, Neurology. 47:889-894, 1996). Failure to respond to IFN-β is not a rare event, and therefore it is important to identify suitable combinations of standard IFN-β therapy with other treatment modalities, and new therapeutic protocols.